P-cyclohexylphenylglycolic acid and derivatives thereof

ABSTRACT

THE COMPOUNDS OF THIS INVENTION ARE NON-STEROIDS. WHEN ADMINISTERED TO MAMMALS, THEY AFFORD SIGNIFICANT INHIBITION IN THE DEVELOPMENT OF INFLAMMATION FROM POLYARTHRITIS AND MANIFEST SIGNIFICANT ANALGESIC AND ANTIPYRETIC ACTIVITIES IN THE TREATED MAMMAL.

J. DlAMoND 3,704,313

P-CYCLOHEXYLPHENYLGLYCOLIC ACID AND DERIVATIVES THEREOF Nov. 28, 1972 .2Sheets-Sheet 1 Filed Oct. l0, 1968 HHH .aan 2 NH QH @aannam HcmEumnuman@ QSQFQHE Si Amman.: UHHHumHE mdouucov nwuoaonou HH .umeoo N msnm H(szuun) Stonuof) panealnun m01; aumIoA :oog u1: aouaxagggq wea"INVENTOR.

Jaua: D mma/v #fra/Mey J. DIAMOND Nov. 28, 1972P-CYCLOHEXYLPHENYLGLYCOLIC ACID AND DERIVATIVES THEREOF Filed oct. 1o.196e .2 Sheets-Sheet 2 2.32.3: uuuum uauE R.

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solnuog) paneanun mol; amnIoA :xoog u; anuaxaggq nea United StatesPatent C" 3,704,313 p-CYCLOHEXYLPHENYLGLYCOLIC ACID AND DERIVATIVESTHEREOF Julius Diamond, Lafayette Hill, Pa., assiguor to William H.Rorer Inc., Washington, Pa.

Filed Oct. 10, 1968, Ser. No. 767,058 Int. Cl. C07c 65/14 U.S. Cl.260--520 6 Claims ABSTRACT F THE DISCLOSURE The compounds of thisinvention are non-steroids. When administered to mammals, they affordsignificant inhibition in the development of inammation frompolyarthritis and manifest significant analgesic and antipyreticactivities in the treated mammal.

This invention relates to p-cycloalkylphenylglycolic acids and moreparticularly to m-halo-pcycl0alkylphenylglycolic acids, their non-toxicsalts and lower alkyl esters.

The p-cyc1oalkylphenylglycolic acids, their non-toxic salts and estershave the formula (tI-COOM l R1 X l Hsin in which Z is hydrogen; loweralkanoyl of less than 3,704,313 Patented Nov. 28, 1972 v"ii-rye oxide anrn-ha1opcycloalkylphenylglyoxylate having the formula:

in which R3 is a lower alkyl radical having less than 5 carbon atoms andX is a halogen. If R1 of the p-cycloalkylphenylglycolic acid of theFormula l is an alkyl group, the m-halo-p-cycloalkylphenylglyoxylate ofFormula 2 above is reacted with a Grignard Reagent having the formula:

(3) RlMgX in which R1 is lower alkyl having less than 5 carbon atoms andX is halogen. I'he reaction product of m-halopcycloalkylphenylglyoxylate of Formula 2 above with hydrogen or with theGrignard Reagent is then hydrolyzed to produce the desiredp-cycloalkylphenylglycolic acid. The pcycloal'kylphenylglycolic acid isthen reacted in the presence of a tertiary amine, such as pyridine,picoline, or quinoline, with an alkanoyl chloride or aroyl chloridehaving the formula:

'RCOCl in which R is lower alkyl, having less than 5 carbon atoms, oraryl such as phenyl, p-chlorophenyl, or tolyl.

'Ihe reaction which takes place with them-halo-pcycloalkylphenylglyoxylate with either hydrogen or the GrignardReagent and the subsequent hydrolysis and acylation is represented asfollows:

H21. C o C O 0 R Hart) '-1 Rim carbon atoms or; aroyl of less than 8carbon atoms; R1 is hydrogen or lower alkyl of less than 5 carbon atoms;M is hydrogen, sodium, or a lower alkyl of less than 5 carbon atoms; Xis a halogen or triuoromethyl; and n is 0, l or 2.

Examples of the lower alkyl are methyl, ethyl, isopropyl and n-butyl.Any one of the halogens-chlorine, bromine, iodine or fluorine-may beused. Examples of aroyl are benzoyl, p-chlorobenzoyl, toluoyl. Examplesof lower alkanoyl are acetyl, propionyl, n-butyryl and isobutyryl.

The p-cycloalkylphenylglycolic acids may be produced by reacting withhydrogen in the presence of platinum Them-halo-p-cycloalkylphenylglyoxylate (2) may be prepared by initiallyreacting, desirably at 16-18 C., cycloalkylbenzene with a lower alkyloxalyl chloride in the presence of anhydrous aluminum chloride toproduce an unhalogenated derivative. The reaction which takes place isrepresented by the following:

in which R3 is a lower alkyl.

AlClx The unhalogenated derivative is then halogenated to the derivativeof Formula 2 by subjecting it to iodine dissolved in an inert solvent,such as carbon tetrachloride. To the resulting solution is added asolution of the halogen in an inert solvent, such as carbontetrachloride. Desirably, the solution of the required halogen is addeddropwise to the solution of the unhalogenated derivative and iodine.Preferably, the addition is conducted by maintaining the temperature ofthe reaction mixture near C. The reaction which takes place is asfollows when chlorine is the halogen to be substituted:

The sodium or potassium non-toxic salts of this invention are producedby reacting approximate stoiohiometric amounts of the alkali hydroxides,alkali carbonates, or alkali bicarbonates, and the required quantity ofm-halocycloalkylphenylglycolic acids.

The compositions of this invention manifest significant anti-inammatoryactivity in polyarthritis when administered to a mammal in dosages of 1to 100 milligrams per kilogram of body weight per day. The compositionsof this invention also increase the pain-threshold and reduce fever whenadministered to mammals. Desirably, the compounds of this invention 4(l)are associated with solids or liquid pharmaceutically acceptablecarriers for oral or parenteral administration in the treatment ofarthritis or pain. The compounds may be in the form of capsules,tablets, powders, sterile solutions of water or other solvents or otherdosage forms. The compounds may be admixed with diluents and adjuvants,such as lactose, gums, stearic acid or talc. One or a plurality ofcompounds of this invention may be administered to the mammal.

The compounds of this invention contain an asymmetric carbon atom and,as initially prepared, are the racemates composed of equal parts of thedextrorotary and levorotary stereoisomers of each such compound. Theracemates of two of the compounds-m-chloro-p-cyclohexylphenylglycolicacid (Compound iI) and m-chloro-p-cyclohexyl a methylphenylglycolic acid(Compound 1V)- were prepared and each was separated into its respectivedextrorotary and levorotary stereoisomers by reacting the racemate withan optically active base, for example, cinchonidine, separating thediastereomerio salts by fractional crystallzation, and hydrolyzing thesalts with dilute hydrochloric acid. As later shown, the dextrorotarystereoisomer of each compound showed signilicantly greater activity fromthe corresponding levorotary stereoisomer and racemate when testedpharmacologically. The dextrorotary stereoisomers of Compounds I and IV,in their overall prole, showed an activity greater than aspirin andphenylbutazone and approached the activity of indomethacin. While thedextrorotary stereoisomer of Compound lV was more active than thedextrorotary stereoisomer of Compound I in Polyarthritis, Ultra VioletErythema and Filter Paper Granuloma assays, it also showed less adverseeffects than the corresponding dextrorotary stereoisomer of Compound I.

A more comprehensive understanding of this invention is obtained byreference to the following examples:

EXAMPLE I Preparation of dl-m-chloro-p-cyclohexylphenylglycolic acidStage A. Preparation of p-cyclohexylphenylglyoxylic acid ethylester.-Qfclohexylbenzene 53 g. (0.33 mole) and 50.5 g. (0.37 mole) ofethyl oxalyl chloride were dissolved in 200 ml. of dry1,l,2,2tetrachloroethane (dried over anhyhdrous MgSO4 overnight).Anhydrous AlCl3 52 g. (0.39 mole) was added in small portions to thereaction mixture with stirring over 2 hours. During the addition, thetemperature of the mixture was maintained between 1618 C. The mixturewas stirred for an additional hour and allowed to stand overnight. Thedark red solution was then slowly poured into 1500 ml. of iced salinesolution with stirring. After standing, two layers formed. The aqueouslayer was extracted with 500 ml. of ether and the ether extract wascombined with the organic layer which was dissolved in 1500 ml. of etherand separated. The ether solution was washed with 10X 100 ml. portionsof a 1:1 mixture of saturated NaCl solution and 10% HCl solution, and 5X100 ml. portions of water. The ether solution was then dried overanh'ydrous MgSO4 for 1 hour and tiltered. The solvents were removed bydistillation under reduced pressure. Distillation of the residue at16S-167 C. (1.1 mm.) gave 67.6 g. (80.7%) of yellow liquid product ND251.5398.

Stage B. Preparation of rn-chloro-p-cyclohexylphenylglyoxylic acid ethylester.p-Cyclohexylphenylglyoxylic acid ethyl ester 98.9 g. (0.38 mole)and 6:1 g. of iodine (0.048 mole) were dissolved in 99 ml. of carbontetrachloride. To this solution a solution of 40.4 g. (0.59 mole) of C12in 365 ml. of VVcarbon tetrachloride was added dropwise over a period of2 hours. During the addition, the temperature of the reaction mixturewas maintained at 0 C. The red-'brown mixture was stirred for 3 hoursand allowed to stand overnight gradually warming to room temperature.The solvent and lCl were removed by distillation under reduced pressure.The residue was distilled at 190 C. (2.7 mm.) and 186.5u C. (1.9 mm.).

Analyss.-Calcd. for C10H19Cl03: C1, 12.03%; rfound: Cl, 13.47%. Yield:94:8 g. (84.6%).

Stage C. Preparation of dl-m-chloro-p-dyelohexylphenylglycolic acid-Intoa Paar hydrogenation bottle was added 42.4 g. (0.144 mole) ofm-chloro-p-cyclohexylphenylglyoxylic acid ethyl ester, 2 ml. of 0.1M-FeSO4 solution; 220 m1. of isopropanol, and 1.0 g. of 84.1% PtOz. Themixture was shaken for 2 hours at room temperature with hydrogen gas(initial pressure 57 p.s.i.). The hydrogen uptake was 112% of theory atthe end of 2 hours. The catalyst was filtered olf. After adding 38 g.(0.7 mole) of KOH to the filtrate, it was heated at reflux temperaturein a nitrogen atmosphere. The solution was concentrated in vacuo to aviscous oil, which was dissolved in 500 ml. of Water, treated withNorit, and filtered through Celite 545. The iiltrate was acidified with10% HC1, and the precipitate was taken up in ether. The ether layer wasdried over MgSO4, treated with Norit, filtered through Celite 545, andthe filtrate concentrated to a ml. volume. Cyclohexane ml. was added,and the solution was again concentrated to a 100 m1. volume, cooled toroom temperature, and the white precipitate was collected and .washedwith 3X 20 m1. cyclohexane. 'Ihe solid was dried at 110 C. -for 2 hours.Yield: 27.5 g. (71.0%) M.P. 14C-2 C. dec. Recrystallization from benzenecyclohexane '155 gave a white product. Yield: 26.2 g. (67.7%) M.P.'142-3 C. dec.

Analysis- Calci for CMHlqClOa (percent): C=62.57, H=6.38, Cl= 12.19.Found (percent): C=62.94, H=6.40, Cl=12.58.

EXAMPLE II Preparation of l-m-chloro-p-cyclohexylphenylglycolic acid Toa boiling solution of 29.4 g. (0.10 mole) of cinchonidine in l liter ofabsolute ethanol was added a boiling solution of 26.9 g. (0.10 mole) ofdl-m-chloro-pcyclohexylphenylglycolic acid in 500 ml. of absoluteethanol. The solution was stirred briey then allowed to cool to roomtemperature overnight. The white crystalline precipitate was collectedand washed with 2X 25 Inl..

5 of ethanol and air dried. Yield 36.9 g. (65.5%). M.P. 234-5 C.Recrystallization from 3 liters of isopropanol gave white needlecrystals; yield 16.1 g. (28.6%). M.P. 242-4 C. dec. This material washydrolyzed with 200 ml. of 1.2 N-HCl. The white solid was collected,washed with 3X 50 m1. water and dried at 55 C. overnight; yield 7.5 g.(27.9%). Recrystallization from CsHs/CGHm (75:50) gave 6.5 g. (24.2%)white solid, M.P. 147-50 C. dec. [ab -75 (c.-=C2H5OH). A secondrecrystallization from C6H5/C6H12 (125 :100) gave 5.5 g. (20.4%), M.P.15S-60 C. dec.

Analysis-Caled. for C14H17C1O3 (percent): C=62.57, H=6.38, Cl= 13.19.Found (percent): C= 62.67, H=6.33, Cl=12.87.

EXAMPLE III Preparation of d-m-chloro-p-cyclohexylphenylglycolic acidThe combined ethanol and isopropanol filtrates from Example II wereevaporated to dryness. Yield, 35 g. (62.2%). M.P. 23S-7 C. dec. Thismaterial was triturated with 1 liter of boiling acetone. The materialwhich did not go into solution was filtered off; yield 25 g. (44.4%).M.P. 230-40 C. dec. The filtrate was evaporated to dryness; yield 10.0g. (17.8%). M.P. 2li-15 C. dec. This material was hydrolyzed with 100ml. of 1.2 N-HCl. The white crystalline precipitate was co1- lected,washed with 3X 25 ml. of water, and dried at 55 C., yield 4.8 g.(17.8%). M.P. 15S-9 C. dec. Recrystallization from C6H6/C6H12 (75:50)gave 4.3 g. (16%). M.P. 15S-60 C. dec., [adn +82.5 (c.'=l, C2H50H).

Analyss.-Calcd. for C14H17Cl03 (percent): C=62.57, H|= 6.38, Cl= 13.19.Found (percent): Cv= 62.75,

H=6.42, Cl=13.30.

EXAMPLE IV lPreparation ofdl-m-chlorop-cyclohexyl-a-methyl-phenylglycolic acid Methylmagnesiumiodide solution was prepared from 6.7 g. (0.047 mole) of methyl iodide,1.24 g. (0.051 g.- atom) of magnesium turnings, and 40 m1. of anhydrousether. This solution was added over a period of 1 hour to a solution of15 g. (0.0508 mole) of m-chloro-pcyclohexylphenylglyoxylic acid ethylester. The addition was carried out with vigorous stirring at to 5 C.The red-brown solution was then allowed to stand at room temperatureovernight. The mixture was poured into an ice-cold solution of 0.2MH2SO4. The ether layer was separated, extracted with 3X 70 ml. of 1%H2804, dried over MgSO4, filtered, and evaporated. Yield 16.9 g.redbrown oil. The oil was reliuxed for 3 hours under N2 with a solutionof 100 ml. of 10% Na2CO3 and 20 ml. of ethanol. After cooling to roomtemperature, the solution was treated with Norit, filtered, andevaporated. The solid residue was crystallized from benzene 25:cyclohexane 230 to give a white crystalline precipitate which wascollected on a filter, washed 3X 25 ml. cyclohexane, and dried at 98/0.1mm. for 3 hours. Yield 8.0 g. (55.6%), M.P. 149.5-150.5 C. dec.

Analyss.-Calcd. for C15H19Cl03 (percent): C=63.71, H= 6.77, Cl= 12.54.Found (percent): C=63.52, H=6.62, Cl=13.16.

EXAMPLE V To a boiling solution of 20.3 g, (0.069 mole) of cinchonidinein 2 liters of acetone was added 19.5 g. (0.069 mole) ofdlm-chloro-p-cyclohexyl-a-methyl-phenylglycolic acid dissolved in 250ml. of acetone. The resulting mixture was refiuxed for minutes andiltered hot; yield 21 g. (52.8%), M.P. 232-3" C. dec. Trituration with2X 500 ml. of acetone at room temperature gave 19.3 g. (48.5%), M.P. 232C. dec. The cinchonidine salt was hydrolyzed with"200 ml. of 1.2 lN-HCl,filtered, washed with 3X 50 ml. water, and dried at 80; yield 9.0 g.(46.1%), M.P. l26-33 C. dec. [011D 16 (c.=1, CZHQOH). Recrystallizationfrom n-heptane gave 6.2 g.31.8%),M.1 128 C. dec., 10.1 31.5 C. (c.=1,C2H5OH).

Analyss.-Calcd. for C15-H19C1O3 (percent): C=63.71, H 6.77, Cl 12.54.Found (percent): C 64.40, H=7.00, 0:12.44.

EXAMPLE VI Preparation of d-m-chloro-p-cyclohexyl-u-methylphenylglycolicacid The acetone filtrate from Example V was cooled to room temperatureto give a white precipitate which was collected; yield 2.2 g. (5.5%),M.P. 220-221 C. dec. The filtrate was taken to dryness, triturated withml. of ether, filtered and dried at 50 C.; yield 13.5 g. (33.9%), yellowcrystals, M.P. 212-13 C. dec. The cinchonidine salt was hydrolyzed with100 ml. of 1.2 N-HCl, filtered, washed wtih 3X 50 ml. water, and driedat 80 C.; yield 6.5 g. (33.3%), M.P. 126-8 C. dec., [a]D +35 (c.=1,CZHSOH).

AnaIyss.-Calcd. for C15H19Cl03 (percent): C=63.7l, H 6.77, Cl= 12.54.Found (percent): C 63.77, H=6.67, Cl=12.71.

EXAMPLE VII Preparation ofd-m-chloro-p-cyclohexyl-a-methylphenylglycolic acid benzoate Thecompound from Example VI, 5.66 g. (0.02 mole), is dissolved in 30 ml. ofdry pyridine and 2.5 ml. (0.022 mole) of benzoyl chloride is addeddropwise while stirring at 0 C. After 1 hour at 0 C., the reactionmixture is allowed to warm to room temperature, and poured into excesscold, dilute hydrochloric acid. The mixture is extracted with n-hexane,and the hexane extract is washed with water, then dried over anhydrousMgSO4 and filtered. Evaporation of the solvent from the filtrate leavesthe benzoate.

The benzoate was purified by trituration with acetic acid. Yield: 2 g.;M.P. 1314 C. dec., [11],; +10 C. (c.=1, C2H5OH).

EXAMPLE VIII Corresponding pcycloalkylphenylglycolic acid in which n is0 or 2 of Compound 1 Such corresponding compounds are prepared in thesame manner as the compounds of. Examples I through VII, except that thestarting material is a cyclopentyl or cycloheptyl compound.

Brief descriptions of the pharmacological tests conducted are givenbelow:

CARRAGEENIN PAW EDEMA Of the substances used to induce local irritation,carrageenin was selected since most known non-steroidalanti-inflammatory agents inhibit this inflammation.

Ten male rats per dose group (-150 grams) were given one-half of thetest material orally. Thirty minutes later, the remainder of the dosewas given and 0.2 ml. of a 1% carrageenin solution was injectedsubdermally into the plantar surface of the hind paw. Each paw is markedas a consistent anatomical site, then immersed in a mercury bath to thatpoint. The mercury bath is connected to a pressure transducer and thevolume of displacement is read directly on a recorder. Three hours afterdrug administration, the hind paw volume is measured again. Theincreased volume is an index of edema. Treated groups are compared to aplacebo-treated group to calculate the percent inhibition of edema.

FILTER PAPER GRANULOMA This assay was used to evaluate anti-inflammatoryagents and to determine the lowest dose which produces significantinhibition of granuloma growth. This assay has the advantage of beingsemi-acute (4-7 days). The usual end point involves obtaining the wetweight as well as the dry weight of the granuloma.

Small discs of filter paper saturated 'With carrageenn were placedsubcutaneously in each rat on the first day of the study. Test compoundwas administered orally on a B.I.D. basis on Day l to Day 4. On Day 5, asingle dose was given in the morning and the animals were sacrificed inthe afternoon. Both filter paper discs were removed and trimmed ofextraneous tissue and then weighed. After drying in an oven over theweekend, the dry weight was obtained. Activity was determined by thedifference in granuloma weight between a placebo-treated control groupand the drug-treated groups.

RANDALL-SELITTO ANALGESIA TEST In accordance with the Randall-Selittotest for measuring the pain threshold, the pressure needed on a metalplunger to a give a pain response in a rat when the plunger is placed inthe yeast-inflamed hind paw of a rat is measured. Following measurementof control pain threshold, yeast was injected into the paw and the testcompound was given orally. The pain threshold was measured at hourlyintervals and compared to a placebotreated control group.

ANTI-PYRETIC ASSAY Brewers yeast was injected subcutaneously in rats andrectal temperatures were obtained at the end of flve hours. Those rats(l per group) having a significant fever were given test compounds andrectal temperatures were measured at hourly intervals for 2-3 hours. (Apositive response occurs when rectal temperature decreases by 1 C. ormore.)

-PHENYLQUINONE ANALGESIA Mice were pre-treated orally with test compoundand then given 1.25 mg./kg. phenylquinone i.p. to produce a series ofwrithes (severe intestinal contractions). The number of writhes wasrecorded. The percent decrease was calculated from the incidence ofwrithes in a placebo-treated control group.

8 ULTRA-VIOLET ERY'DHEMA IN GUINEA PIGS Erythema associated withinflammation was used in the assay. Restricted areas of a guinea pigwere exposed to a controlled ultraviolet light and after two hours, theexposed areas were graded for the extent of erythema.

POLYARTHRITIS IN RATS Twelve rats per dose group were treated (B.I.D.)starting the day before injection of adjuvant. Paw volumes were measuredfor both hind paws on several days during and following drug treatment.Drug was given for a period of 15 days. The paw volume was compared toan untreated control group to determine volume increase. Drug action wascalculated as the percent decrease in paw volume (inflammation) ascompared to an adjuvanttreated control. Gross signs of inflammation werescored on a weekly basis and drug action calculated as a decrease intotal score. Body weights were recorded at intervals.

GASTRIC IRRITATION Rats fasting for 48 hours were tested. The drug wasgiven orally and the animals sacrificed at the end of five hours. Thestomachs were examined for irritation and the animals were gradedpositive or negative and ED50 values calculated.

The results of these tests, and a comparison with standard drugs, aregiven in Tables I, II and IIII, and FIGS. A and B, which are shown onthe accompanying drawings.

FIG. A indicates the effect of compounds II, III and VI on the volume ofthe adjuvant-treated hind paw (right); and

FIG. B indicates the effect of compounds II, III and VI on the volume ofthe contralateral hind paw (left).

LEGEND FOR TABLE III PQW Phenylquinone writhing. RSA Randall-Selittoanalgesia. CPE Carrageenin paw edema. UVE Ultra violet erythema. FPGFilter paper granuloma. AP Anti-pyresis.

P.T Pain threshold.

#P/T Number positive/total.

TABLE L-SUMMARY OF ANTI-INFLAMMATORY ASSAYS Filter paper PhenylqulnoneUltra violet granuloma writhing Randall-Selitto Carrageenln erythemaAnti-pyresis analgesia paw edema Percent Dose, Number decrease NumbermgJkg., Percent Dose, Percent Dose, Percent Dose, positive] Dose,intlam- Dose, positive Test compound p.o. decrease mgJkg. increasemg./kg. decrease Ing/kg. total Ing/kg. mation mg./kg. tota dlm-Chloropcyclohexylphenyiglycolic acid 10 45 50 95 60 38 10 3/8 50 12 10 2/8 2041 100 94 100 35 25 5/8 100 35 25 6/8 25 46 35 50 7/7 40 88 50 100 6/680 97 150 95 ED50= ED50=18 d-mChloro-p cyclohexylphenylglycolic acid 6.25 46 12. 5 2/8 12. 5 48 25 3/8 25 83 50 6/8 50 100 100 7/8 ED5= 10ED50=28 l-m-Chloro-pcyclohexylphenylglycolic acid 37. 5 0 18. 75 0/8 1637. 5 3/8 150 12. 2 75 4/8 300 77 150 5/8 ED50=195 ED50=75 dl-m-Chloro-pcyclohexylamethylphenylglycolic acid 10 34 50 74 50 l. 0 10 4/8 50 23 102/8 2O 50 100 82 100 15. 0 25 7/8 100 24 20 3/8 50 7/8 8/8 10o 8/8 TABLEI-Continued Filter paper Phenylquinone Ultra violet granuloma.

Writhing Randall-Selitto Carrageenin erythema Anti pyresis analgesic pawedema Percent Dose, Number decrease Number mg./kg., Percent Dose,Percent Dose, Percent Dose, positive/ Dose, inam- Dose, positive] Testcompound p.o. decrease mgJkg. increase mgJkg. decrease mgJkg. totalmgJkg. mation nig/kg. tota d-m-Chloro-pcyclohexyhxmethylphenylglycoiicacid 12.5 4i 12.5 4s 12 5 1/8 25 3s 25 57 3/8 50 45 50 57 50 5/8 100 5e100 50 100 7/8 ED50=35 ED55=35 1-mChloro-pcyc1ohexyl-amethylphenylgiycolic acid 25 31 12.5 30 50 15 10 4/8 0 12. 50/8 50 20 25 23 100 22 25 7/8 10o 29 25 1/8 100 49 50 25 35 8/8 50 1/8150 50 100 36 100 3/8 ED50=100 EDwio ED5= 100 TABLE II 3. A compound ofclaim 1 in which the compound Gastric irritation levorotary y Testcompound: ED50 ,ngc/kg. 25 4. A compound of claim 2 which isd-m-chloro-pdl m Chloro p cyclohexylphenylglycolicCYClOhXYlPhCDYlglYCOllC aff1d I acid 7 5. A compound of claim 3 which 1sl-m-chloro-pdl -mChloro-p-cyclohexyl-a-methylphenylcyclohexylphenylglycolic acid.

glycolic acid 59 6. A compound of claim 1 which is dl-mchloro-pd-m-Chloro-p-cyclohexyl a-methylphenylgly- 30 cyclohexylphenylglycolicacid.

colic acid 21.5 l-m-Ch1orop-cyclohexyl a methylphenylglycolic acidAspirin 36 r Indomethacin 1-2 3 *Estimatedl TABLE IIL-ANTI-INFLAm/IATORYACTIVITY F STANDARD DRUGS P.Q.W. Reni., A1. percent C.P.E. U.V.E.F.P.G.,-- Dose, Percent ED, PT percent ED, percent EDN, Test compoundmgJkg. Route l mg./kg. T L mgJkg. l #PIT nig/kg.

Aspirin Po as als 15 25 P0 6/8 50 P0 2i 6/8 75 Po 100 ABo 19 SIB o P0818 200. P0 49 400 Po 62 800 P0 54 Indo-methacin .1 P0 0.97

.5 Po .625 P0 1.25 P0 15 2.5 P0 27 5.0 P0 47 10.0 P0 47.5 2/8 14 20.0 P049 6/8 30.0 PO 7/8 40.0 P0 7/8 Phenyl-butezone- P0 3.8

P0 44-.; 0-20 ils 100 100 P0 50 v 6/8 150 P0 200 P0 71 6/8 300 P0 400 Po69 8/8 The compounds of this invention may be administered ReferencesCited to a mammal in the form of a pharmaceutically ascept- UNITEDSTATES PATENTS able salt, 1n the form of tablets, injectable ampoules,sup- 3,435,075 3/1969 G1 amkowski 260 590 positories, saccharme,granules, syrup or other dosage un forms' LORRAINE A. WEINBERGER,Primary Examiner What is claimed 1s: 0

1. A compound which is m-chloro-p-cyclohexylphenyl- F TERAPANE,ASSSfallt EXamIler glycolic acid or non-toxic salt or loweralkyl esterthereof U S C1 X R of less than 5 carbon atoms.

2. A compound of claim 1 in which the compound is 260-284, 469, 473 A,476 R, 488 CD; 424-308, 311 dextrorotary. 317

